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1.
BMC Complement Altern Med ; 19(1): 325, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752825

RESUMO

BACKGROUND: Osteoarthritis (OA) is an age-related joint disease with characteristics that involve the progressive degradation of articular cartilage and resulting chronic pain. Previously, we reported that Astragalus membranaceus and Lithospermum erythrorhizon showed significant anti-inflammatory and anti-osteoarthritis activities. The objective of this study was to examine the protective effects of ALM16, a new herbal mixture (7:3) of ethanol extracts of A. membranaceus and L. erythrorhizon, against OA in in vitro and in vivo models. METHODS: The levels of matrix metalloproteinase (MMP)-1, -3 and - 13 and glycosaminoglycan (GAG) in interleukin (IL)-1ß or ALM16 treated SW1353 cells were determined using an enzyme-linked immunosorbent and quantitative kit, respectively. In vivo, the anti-analgesic and anti-inflammatory activities of ALM16 were assessed via the acetic acid-induced writhing response and in a carrageenan-induced paw edema model in ICR mice, respectively. In addition, the chondroprotective effects of ALM16 were analyzed using a single-intra-articular injection of monosodium iodoacetate (MIA) in the right knee joint of Wister/ST rat. All samples were orally administered daily for 2 weeks starting 1 week after the MIA injection. The paw withdrawal threshold (PWT) in MIA-injected rats was measured by the von Frey test using the up-down method. Histopathological changes of the cartilage in OA rats were analyzed by hematoxylin and eosin (H&E) staining. RESULTS: ALM16 remarkably reduced the GAG degradation and MMP levels in IL-1ß treated SW1353 cells. ALM16 markedly decreased the thickness of the paw edema and writhing response in a dose-dependent manner in mice. In the MIA-induced OA rat model, ALM16 significantly reduced the PWT compared to the control group. In particular, from histological observations, ALM16 showed clear improvement of OA lesions, such as the loss of necrotic chondrocytes and cartilage erosion of more than 200 mg/kg b.w., comparable to or better than a positive drug control (JOINS™, 200 mg/kg) in the cartilage of MIA-OA rats. CONCLUSIONS: Our results demonstrate that ALM16 has a strong chondroprotective effect against the OA model in vitro and in vivo, likely attributed to its anti-inflammatory activity and inhibition of MMP production.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Cartilagem Articular/efeitos dos fármacos , Osteoartrite , Extratos Vegetais/farmacologia , Animais , Astragalus propinquus/química , Cartilagem Articular/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glicosaminoglicanos/análise , Humanos , Ácido Iodoacético/efeitos adversos , Lithospermum/química , Masculino , Metaloproteinases da Matriz/análise , Medicina Tradicional do Leste Asiático , Camundongos Endogâmicos ICR , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Substâncias Protetoras/farmacologia , Ratos
2.
Fitoterapia ; 134: 329-339, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30858045

RESUMO

Shikonin is a natural compound isolated from herbs and traditional medicines that have been used in a number of countries to treat various illnesses including inflammation, virus infection and cancer for centuries. Recent studies have shed light on the molecular mechanisms underlying these biological activities of Shikonin. Here we review the latest advances in our understanding of this compound class in the anti-cancer regimen. We focus on signaling pathways and cellular targets involved in the anticancer activity of Shikonin. We also briefly discuss approaches in evaluating the in vivo bioactivity and drug delivery of Shikonin in the anti-cancer treatment. Subsequently, we highlight recently developed strategies in the chemical and biogenic synthesis of Shikonin and summarize the structure-activity relationship studies of Shikonin. We anticipate that these lines of information would facilitate the functional identification and future clinical development of Shikonin and its derivatives in the combat against cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/síntese química , Sistemas de Liberação de Medicamentos , Humanos , Lithospermum/química , Naftoquinonas/síntese química , Raízes de Plantas/química
3.
J Ethnopharmacol ; 235: 406-414, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30703490

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lithospermi radix has been prescribed in traditional folk medicine to treat diverse diseases like cancer. AIM OF THE STUDY: The present study assessed the sub-chronic oral toxicity of an aqueous extract of lithospermi radix (WLR) in Fischer 344 rats over a period of 13 weeks. MATERIALS AND METHODS: The chemical compositions of WLR were analyzed using ultra-high performance liquid chromatography (UHPLC). WLR was daily administered to Fischer 344 rats at 0, 500, 1000, and 2000 mg/kg body weights (bw) for 13 weeks via oral gavage. Changes in mortalities, body weights, and intakes of food and water were monitored during the WLR treatment period. Urine was collected and analyzed 12 h before necropsy. Organ weights, hematological parameters, and plasma biochemical parameters were determined along with histopathological examination. RESULTS: When compared with the normal control group, no remarkable toxic signs or parameter variations related with WLR treatment were observed in mortality, body weights, organ weights, food and water consumptions, urinalysis, hematological and plasma biochemical analyses, and histopathological examination. Mortalities observed in one male at 2000 mg/kg bw and three females at 1000 mg/kg bw were not related with WLR treatment because no gross findings of toxicity were observed in both morphological and histological examination. Some significant changes in clinical parameters or histological lesions observed in WLR-treated animals were not related with WLR treatment because the differences were marginal and did not show dose-dependent or directional changes. CONCLUSIONS: Based on these findings, the calculated no-observed-adverse-effect-level (NOAEL) in rats was higher than 2000 mg/kg bw.


Assuntos
Lithospermum/química , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/toxicidade , Testes de Toxicidade Subcrônica , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Masculino , Medicina Tradicional , Nível de Efeito Adverso não Observado , Extratos Vegetais/administração & dosagem , Raízes de Plantas , Ratos , Ratos Endogâmicos F344
4.
Mater Sci Eng C Mater Biol Appl ; 96: 850-858, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30606599

RESUMO

This study examined the in vitro characteristics and in vivo wound healing effect of novel Lithospermi radix (LR) extract-containing bilayer scaffolds in a rat model. LR extract, which has been used as a traditional herbal medicine for treating skin wounds, was added to a biocompatible gelatin solution. After glutaraldehyde vapor was used to modify the surface of chitosan scaffolds, various ratios of mammalian gelatin and fish collagen (GF100, GF91 and GF82) were electrospun onto the chitosan scaffolds to manufacture bilayer scaffolds. The porous chitosan scaffolds with a high swelling ratio showed efficient exudate absorption ability. GF91 gelatin nanofibers electrospun at a constant flow rate at 0.1 mL/h and a voltage of 20 kV displayed the optimal characteristics required for cell attachment and skin tissue regeneration. Moreover, the LR extract was successfully released slowly from the GF91 nanofibers. The investigation of the wound-healing activity of the chitosan/gelatin (CGF) bilayer scaffolds revealed that CGF91L provided the highest wound recovery rate in vivo in Sprague-Dawley (SD) rats. Based on its wound-healing effect and beneficial characteristics, the novel LR extract-containing CGF91 bilayer scaffold demonstrates potential as a material for treating skin wounds.


Assuntos
Lithospermum/química , Nanofibras , Extratos Vegetais , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Linhagem Celular , Quitosana/química , Quitosana/farmacologia , Modelos Animais de Doenças , Implantes de Medicamento , Masculino , Camundongos , Nanofibras/química , Nanofibras/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
5.
Nat Prod Res ; 33(12): 1691-1698, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29382220

RESUMO

One new furylhydroquinone derivative (1) and seven known compounds (2-8) were isolated from the roots of Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae). The structure of 1 was elucidated by extensive spectroscopic methods using NMR and MS. The absolute configuration of shikonofuran J (1) was unambiguously determined by aid of comparison experimental ECD with predicted ECD spectra. All the isolates were tested for their inhibitory activities against IL-6 production in HaCaT cells stimulated by tumor necrosis factor (TNF)-α. It was found that gracicleistanthoside (5) and uridine (7) remarkably down-regulated the TNF-α-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation, in HaCaT cells.


Assuntos
Anti-Inflamatórios/farmacologia , Hidroquinonas/isolamento & purificação , Lithospermum/química , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Humanos , Hidroquinonas/farmacologia , Interleucina-6/biossíntese , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Raízes de Plantas/química , Fator de Necrose Tumoral alfa/farmacologia
6.
Appl Biochem Biotechnol ; 187(3): 744-752, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30054862

RESUMO

The benefits of Lithospermum officinale has encouraged people to continue using its extract (CAS 90063-58-4) in both medicinal and cosmetic industries despite the fact that chemical analysis confirms the presence of pyrrolizidine alkaloids (PAs) in the extract. While the cultivation of L. officinale takes, at least, 2 years to produce usable crops, its callus culture proliferated 8.3 times with 4.9-fold biomass in less than 30 days under the applied conditions in this study. Under the applied conditions, the cell extract contained no toxic PAs while phenylpropanoid pathway was active toward phenolic acids formation not toward naphthoquinone derivatives. Rosmarinic acid was produced as the main constituent. Total phenolic content and antioxidant capacity of the proliferated cell extracts were similar to those of the extracts of the natural plant tissues, in particular from the root. These results support the idea that the extract of L. officinale cells can be a reliable substitute for the extract of the natural plant tissues.


Assuntos
Depuradores de Radicais Livres/química , Lithospermum/química , Lithospermum/citologia , Extratos Vegetais/química , Técnicas de Cultura de Células , Fenóis/análise , Alcaloides de Pirrolizidina/análise
7.
Biol Pharm Bull ; 41(11): 1659-1666, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381665

RESUMO

Lymphangiogenesis, the formation of lymphatic vessels from preexisting ones, promotes cancer growth and metastasis. Finding natural compounds with anti-lymphangiogenic activity will be useful for preventive treatment of lymphatic metastasis. Shikonin, an ingredient of a traditional Japanese and Chinese medicinal herb Lithospermum erythrorhizon, has been widely used in several pharmaceutical and cosmetic preparations, as well as in food colorants. Shikonin has been reported to inhibit lymphangiogenesis in vitro, but the mechanism of inhibition has not been determined. The aim of this study is to investigate the mechanism of anti-lymphangiogenesis of shikonin in primary human lymphatic endothelial cells (HMVEC-dLy). Shikonin, at non-toxic concentrations, significantly inhibited cord formation ability of lymphatic endothelial cells in a dose- and time-dependent manner. Western blotting analysis showed that shikonin decreased nuclear factor-kappaB (NF-κB) activation, as indicated by phosphorylation and nuclear translocation of NF-κB p65, and also reduced both mRNA and protein levels of hypoxia-inducible factor-1 (HIF-1)α. Use of an NF-κB inhibitor (BAY 11-7085) and HIF-1α small interfering RNA (siRNA) transfection revealed that NF-κB activation was upstream of HIF-1α expression, which controls cord formation by HMVEC-dLy. In addition, the reduction of vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3) mRNA levels were also found in HMVEC-dLy that treated with shikonin. In conclusion, shikonin inhibits lymphangiogenesis in vitro by interfering the NF-κB/HIF-1α pathway and involves in suppression of VEGF-C and VEGFR-3 mRNA expression.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lithospermum/química , Linfangiogênese/efeitos dos fármacos , NF-kappa B/metabolismo , Naftoquinonas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metástase Linfática/prevenção & controle , Naftoquinonas/uso terapêutico , Fitoterapia , RNA Mensageiro/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30420490

RESUMO

Acquired resistance of afatinib is a significant challenge for non-small cell lung cancer (NSCLC) therapy and the mechanisms remain unclear. Aberrant activation of epidermal growth factor receptor (EGFR)-dependent downstream pathways, especially phosphatidylinositol-3-kinases/protein kinase B (PI3K/Akt) signaling pathway has been reported to be involved in the occurrence of afatinib resistance. Developing effective anti-cancer agents to overcome afatinib resistance by targetting PI3K/Akt signaling pathway will be a potential strategy for NSCLC treatment. Shikonin is a naphthoquinone compound isolated from the roots of Lithospermum erythrorhizon In the present study, the anti-cancer activity of Shikonin was evaluated on afatinib-resistant NSCLC in vitro and in vivo The data showed that Shikonin inhibited the proliferation and induced apoptosis of afatinib-resistant NSCLC cell line by activating apoptosis signaling pathway and negatively regulating PI3K/Akt signaling pathway. These results revealed that Shikonin was a potential apoptosis inducer in afatinib-resistant NSCLC and a promising candidate for treating patients clinically.


Assuntos
Afatinib/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Afatinib/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Lithospermum/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftoquinonas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Int J Mol Sci ; 19(11)2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30463303

RESUMO

Shiunko ointment is composed of five ingredients including Lithospermi Radix (LR), Angelicae Gigantis Radix, sesame seed oil, beeswax, and swine oil. It is externally applied as a treatment for a wide range of skin conditions such as eczema, psoriasis, hair loss, burns, topical wounds, and atopic dermatitis. Deoxyshikonin is the major angiogenic compound extracted from LR. In this study, we investigated the efficacy of LR extract and deoxyshikonin on impaired wound healing in streptozotocin (STZ)-induced diabetic mice. Treatment with LR extract elevated tube formation in human umbilical vein endothelial cells (HUVECs) and exerted antioxidant activity. An open skin wound was produced on the backs of diabetic mice and was then topically treated with deoxyshikonin or vehicle. In addition, deoxyshikonin promoted tube formation in high glucose conditions exposed to HUVECs, and which may be regulated by increased VEGFR2 expression and phosphorylation of Akt and p38. Our results demonstrate that deoxyshikonin application promoted wound repair in STZ-induced diabetic mice. Collectively, these data suggest that deoxyshikonin is an active ingredient of LR, thereby contributing to wound healing in patients with diabetes.


Assuntos
Diabetes Mellitus Experimental/patologia , Naftoquinonas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lithospermum/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Sci Rep ; 8(1): 13152, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177727

RESUMO

Liver cancer, also known as primary liver cancer, is cancer that starts in the liver. JNU-144, a new meroterpenoid purified from Lithospermum erythrorhizon, has exhibited promising anticancer activity; however, the molecular mechanisms of action of JNU-144 on malignant cells remain unclear. Our studies revealed that JNU-144 suppressed cell viability and proliferation in hepatoma cells by downregulating mTOR activation. Meanwhile, JNU-144 activated the intrinsic apoptosis pathway and subsequently triggered apoptotic cell death in SMMC-7721 cells. We also found that JNU-144 inhibited the epithelial-mesenchymal transition in both SMMC-7721 and HepG2 cells through reprogramming of epithelial-mesenchymal transition (EMT)-related gene expression or regulating protein instability. These findings indicate that JNU-144 exerts potent anticancer activity in hepatoma cells and may be developed as a potential therapeutic drug.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/tratamento farmacológico , Serina-Treonina Quinases TOR/genética , Terpenos/farmacologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos Fitogênicos/isolamento & purificação , Caderinas/genética , Caderinas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos , Lithospermum/química , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Extratos Vegetais/química , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Terpenos/isolamento & purificação , Carga Tumoral/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
11.
Mol Med Rep ; 18(4): 3882-3890, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30106133

RESUMO

As patients with non­small cell lung cancer (NSCLC) and wild­type epidermal growth factor receptor (EGFR) are resistant to treatment with erlotinib or gefitinib, potential chemosensitizers are required to potentiate wild­type EGFR NSCLC cells to erlotinib/gefitinib treatment. The present study reported that shikonin could sensitize the anticancer activity of erlotinib/gefitinib in wild­type EGFR NSCLC cells. Furthermore, shikonin could potentiate mitochondrial­mediated apoptosis induced by erlotinib/gefitinib in wild­type EGFR NSCLC cells. In addition, the present study demonstrated that shikonin could induce apoptosis by activating reactive oxygen species (ROS)­mediated endoplasmic reticulum (ER) stress, and that erlotinib/gefitinib may also induce ER stress in wild­type EGFR NSCLC cells; however, shikonin plus erlotinib/gefitinib was more effective in activating ER stress than either agent alone. This indicated that ROS­mediated ER stress may be associated with enhanced mitochondrial apoptosis induced by shikonin plus erlotinib/gefitinib. In addition, shikonin may promote the transition of cytoprotective ER stress­inducing EGFR­tyrosine kinase inhibitor tolerance to apoptosis­promoting ER stress. Furthermore, shikonin may enhance the anti­NSCLC activity of erlotinib/gefitinib in vivo. The data of the present study indicated that shikonin may be a potential sensitizer to enhance the anti­cancer efficacy of erlotinib/gefitinib in wild­type EGFR NSCLC cells resistant to erlotinib/gefitinib treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/farmacologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Lithospermum/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Naftoquinonas/química , Inibidores de Proteínas Quinases/farmacologia , Espécies Reativas de Oxigênio/metabolismo
12.
BMC Complement Altern Med ; 18(1): 215, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005655

RESUMO

BACKGROUND: Jawoongo is an herbal mixture used in traditional medicine to treat skin diseases. This study aimed to investigate whether Jawoongo ameliorates Atopic dermatitis (AD)-like pathology in mice and to understand its underlying cellular mechanisms. METHODS: AD was induced by 2, 4-Dinitrocholrlbenzene (DNCB) in BALB/c mice. Treatment with Jawoongo was assessed to study the effect of Jawoongo on AD in mice. Histological Analysis, blood analysis, RT-PCR, western blot analysis, ELISA assay and cell viability assay were performed to verify the inhibitory effect of Jawoongo on AD in mice. RESULTS: We found that application of Jawoongo in an ointment form on AD-like skin lesions on DNCB-exposed BALB/c mice reduced skin thickness and ameliorated skin infiltration with inflammatory cells, mast cells and CD4+ cells. The ointment also reduced the mRNA levels of IL-2, IL-4, IL-13 and TNF-α in the sensitized skin. Leukocyte counts and the levels of IgE, IL-6, IL-10 and IL-12 were decreased in the blood of the DNCB-treated mice. Furthermore, studies on cultured cells demonstrated that Jawoongo exhibits anti-inflammatory activities, including the suppression of proinflammatory cytokine expression, nitric oxide (NO) production, and inflammation-associated molecule levels in numerous types of agonist-stimulated innate immune cell, including human mast cells (HMC-1), murine macrophage RAW264.7 cells, and splenocytes isolated from mice. CONCLUSION: These findings indicate that Jawoongo alleviates DNCB-induced AD-like symptoms via the modulation of several inflammatory responses, indicating that Jawoongo might be a useful drug for the treatment of AD.


Assuntos
Angelica/química , Anti-Inflamatórios/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Dinitroclorobenzeno/toxicidade , Lithospermum/química , Extratos Vegetais/administração & dosagem , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/genética , Humanos , Imunoglobulina E/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
13.
Planta Med ; 84(12-13): 920-934, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29843181

RESUMO

Lithospermum officinale is a valuable source of bioactive metabolites with medicinal and industrial values. However, little is known about genes involved in the biosynthesis of these metabolites, primarily due to the lack of genome or transcriptome resources. This study presents the first effort to establish and characterize de novo transcriptome assembly resource for L. officinale and expression analysis for three of its tissues, namely leaf, stem, and root. Using over 4Gbps of RNA-sequencing datasets, we obtained de novo transcriptome assembly of L. officinale, consisting of 77,047 unigenes with assembly N50 value as 1524 bps. Based on transcriptome annotation and functional classification, 52,766 unigenes were assigned with putative genes functions, gene ontology terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. KEGG pathway and gene ontology enrichment analysis using highly expressed unigenes across three tissues and targeted metabolome analysis showed active secondary metabolic processes enriched specifically in the root of L. officinale. Using co-expression analysis, we also identified 20 and 48 unigenes representing different enzymes of lithospermic/chlorogenic acid and shikonin biosynthesis pathways, respectively. We further identified 15 candidate unigenes annotated as cytochrome P450 with the highest expression in the root of L. officinale as novel genes with a role in key biochemical reactions toward shikonin biosynthesis. Thus, through this study, we not only generated a high-quality genomic resource for L. officinale but also propose candidate genes to be involved in shikonin biosynthesis pathways for further functional characterization.


Assuntos
Benzofuranos/metabolismo , Ácido Clorogênico/metabolismo , Depsídeos/metabolismo , Lithospermum/genética , Metaboloma , Naftoquinonas/metabolismo , Transcriptoma , Vias Biossintéticas , Ontologia Genética , Lithospermum/química , Lithospermum/metabolismo , Folhas de Planta/química , Folhas de Planta/genética , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Caules de Planta/química , Caules de Planta/genética , Caules de Planta/metabolismo
14.
Planta Med ; 84(9-10): 674-683, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29642242

RESUMO

Shikonin is the main active principle in the root of Lithospermum erythrorhizon, widely used in traditional Chinese medicine for its anti-inflammatory and wound healing properties. Recent research highlights shikonin's antitumor properties and capacity to prevent acute ulcerative colitis. The aim of the present study was to evaluate the ability of shikonin to prevent, in vivo, the early phases of colorectal cancer development, with special focus on its cytotoxic mechanism in vitro. We employed the azoxymethane/dextran sulfate sodium model of colitis in Balb/C mice. Body weight and drinking were monitored throughout the experiment, and length of colon and lesions of the colon were recorded on termination of the experiment in all of the experimental groups. Colons underwent histological evaluation and biochemical analyses [myeloperoxidase activity assay, measurement of interleukin-6, evaluation of proinflammatory enzymes (cyclooxygenase-2 and inducible nitric oxide synthase), and nuclear factor-κB activation by Western blot]. Caco-2 cells were used to evaluate, in vitro, the effect of shikonin on proliferation, cytotoxicity, cell cycle, and apoptosis. Our results reveal that shikonin significantly protected the intestinal tissue of our animals by preventing the shortening of the colorectum and ulcer formation in a dose-dependent manner. Shikonin attenuated the expression of cyclooxygenase-2 and inducible nitric oxide synthase, and myeloperoxidase activity, and inhibited the production of interleukin-6 and activation of nuclear factor-κB. It induced Bcl-2 and inhibited caspase 3. In conclusion, shikonin acts as a chemopreventive agent in the azoxymethane/dextran sulfate sodium model through inhibition of the proinflammatory milieu generated during the disease, an important risk factor in cancer development.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/prevenção & controle , Neoplasias do Colo/imunologia , Inflamação/prevenção & controle , Doenças Inflamatórias Intestinais/prevenção & controle , Lithospermum/química , Naftoquinonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Azoximetano/efeitos adversos , Células CACO-2 , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/imunologia , Medicina Tradicional Chinesa , Camundongos Endogâmicos BALB C , Raízes de Plantas/química , Cicatrização/efeitos dos fármacos
15.
Helicobacter ; 23(3): e12469, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29520881

RESUMO

BACKGROUND: Burdock complex (BC) constitutes of burdock (Arctium lappa), angelica (Angelica sinensis), gromwell (Lithospermum erythrorhizon), and sesame (Sesamum indicum) oil, which are commonly used in traditional Chinese medicine (TCM) for treating various disorders. This study intended to examine the anti-H. pylori activity of BC on AGS cell model as well as in asymptomatic H. pylori-infected subjects. MATERIALS AND METHODS: AGS cell incubated with H. pylori and treated with BC to evaluate the minimum inhibition concentration (MIC), cell viability (MTT) anti-adhesion activity, and inflammatory markers. In case of clinical trial, H. pylori-positive subjects (urea breath test [UBT] >10%, n = 36) were enrolled and requested to intake BC (n = 19) or placebo (n = 17) for 8 weeks. Antioxidant capacity, total phenol, UBT, inflammatory markers were analyzed at the initial, 4th, 8th, and 10th weeks. Moreover, the endoscopic examination was carried out on baseline and 10th week. RESULTS: In vitro studies showed that BC treatment significantly inhibited (P < .05) the inflammatory markers and adhesion of H. pylori to AGS cell. However, H. pylori-infected subject ingested with BC for 8 weeks significantly decreased (P < .05) the UBT value, inflammatory markers with improved antioxidant activity, and phenolic levels as compared to placebo. Also, consumption of BC considerably healed the ulcer wound. CONCLUSION: Overall, the BC could attenuate H. pylori infection by inhibiting H. pylori adhesion and subsequent inflammatory response on the gastric epithelial cell (AGS) as well as clinically ameliorated UBT, antioxidant capacity, and alleviated inflammation to display its anti-H. pylori activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Úlcera/tratamento farmacológico , Angelica sinensis/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Arctium/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Método Duplo-Cego , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Lithospermum/química , Sesamum/química , Estômago/patologia , Resultado do Tratamento , Úlcera/microbiologia , Úlcera/patologia , Ureia/metabolismo
16.
Mini Rev Med Chem ; 18(2): 164-172, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28245783

RESUMO

Shikonin, alkannin and their derivatives, the main ingredient of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to Inner Mongolian and Northwest of China respectively, hold promising potentials for antitumor effects via multiple-target mechanisms. This review will emphasize the importance of their antitumor activity in apoptosis, necroptosis and immunogenic cell death, and expound the relationship of their antitumor activity and naphthoquinone scaffold that could generate ROS and alkylating agent. Meanwhile, the antitumor mechanisms of naturally-occurring shikonin, alkannin and their derivatives, which were divided into the direct interaction involved in alkylating agent, covalently binding the DNA and protein, as well as the indirect interaction mediated by ROS, nonspecifically influencing the mitochondria or multiple signal pathways, will be systematically summarized and discussed.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Naftoquinonas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lithospermum/química , Naftoquinonas/química , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo
17.
Obesity (Silver Spring) ; 26(1): 126-134, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165897

RESUMO

OBJECTIVE: To examine specific molecular mechanisms involved in modulating hepatic lipogenesis and mitochondria biogenesis signals by Lithospermum erythrorhizon (gromwell) root extract. METHODS: Stable cell lines with luciferase reporter constructs were generated to examine sterol regulatory element binding protein 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma, coactivator 1 (PGC1) α promoter activity and estrogen-related receptor (ERR) α response element activity. Gene expression of SREBP1c, stearoyl coenzyme A desaturase 1, and PGC1α was measured by using reverse transcription polymerase chain reaction. Lipogenesis was measured in human hepatoma cells with Nile red staining and flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) α was determined by using ELISA and Western blot. RESULTS: Gromwell root extract and its naphthoquinones dose-dependently repressed high glucose and liver X receptor α induction of SREBP1c promoter activity and gene expression. Hepatic lipogenesis was repressed, and PGC1α promoter and gene expression and ERRα response element activity were increased by gromwell root extract. Gromwell root extract, shikonin, and α-methyl-n-butyrylshikonin increased AMPKα phosphorylation, and inhibition of AMPK blunted the repression in SREBP1c promoter activity by gromwell root extract and its naphthoquinones. CONCLUSIONS: Data suggest that gromwell root extract and its naphthoquinones repress lipogenesis by increasing the phosphorylated state of AMPKα and stimulating mitochondrial biogenesis signals.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Lithospermum/química , Naftoquinonas/química , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Células CHO , Cricetulus , Células Hep G2 , Humanos , Transfecção
18.
J Sep Sci ; 41(4): 868-876, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29193775

RESUMO

In this study, a green, rapid, and simple method, ionic-liquid-magnetized stirring bar liquid-phase microextraction was developed for the determination of naphthoquinones, including shikonin and ß,ß'-dimethylacrylshikonin, in Zicao. This method permits active magnetic stirring, extraction, and pre-enrichment in a single device simultaneously, so the extract is conveniently collected. The analytes were extracted from the sample to ionic liquid-magnetized stirring bar, then the analyte-adsorbed magnetized stirring bar can be readily isolated from the sample solution by a magnet. The key experimental parameters were investigated and optimized, including the type and volume of ionic liquid, extraction time, salt concentration, stirring speed, and pH. The recoveries were in the range of 89.47-102.38%, and good reproducibilities were obtained with relative standard deviation below 5.36%. Compared with the conventional extraction methods, the proposed method is quicker and more effective.


Assuntos
Medicamentos de Ervas Chinesas/química , Líquidos Iônicos/química , Microextração em Fase Líquida , Naftoquinonas/análise , Boraginaceae/química , Cromatografia Líquida de Alta Pressão , Lithospermum/química , Campos Magnéticos , Conformação Molecular
19.
J Cell Biochem ; 119(1): 748-757, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28657691

RESUMO

Pseudoshikonin I (PSI), a novel biomaterial isolated from Lithospermi radix, has been recognized as an herbal medicine for the treatment of infectious and inflammatory diseases. Bone remodeling maintains a balance through bone resorption (osteoclastogenesis) and bone formation (osteoblastogenesis). Bone formation is generally attributed to osteoblasts. However, the effects of PSI on the bone are not well known. In this study, we found that the ethanol extracts of PSI induced osteoblast differentiation by increasing the expression of bone morphogenic protein 4 (BMP 4). PSI positively regulates the transcriptional expression and osteogenic activity of osteoblast-specific transcription factors such as Runx2 and Osterix. To identify the signaling pathways that mediate PSI-induced osteoblastogenesis, we examined the effects of serine-threonine kinase inhibitors that are known regulators of Osterix and Runx2. PSI-induced upregulation of Osterix and Runx2 was suppressed by treatment with AKT and PKA inhibitors. These results suggest that PSI enhances osteoblast differentiation by stimulating Osterix and Runx2 via the AKT and PKA signaling pathways. Thus, the activation of Runx2 and Osterix is modulated by PSI, thereby demonstrating its potential as a treatment target for bone disease.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Etanol/farmacologia , Lithospermum/química , Osteoblastos/citologia , Fator de Transcrição Sp7/genética , Animais , Proteína Morfogenética Óssea 4/metabolismo , Remodelação Óssea , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Naftoquinonas/química , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Extratos Vegetais/farmacologia , Fator de Transcrição Sp7/metabolismo , Transcrição Genética/efeitos dos fármacos
20.
Biopharm Drug Dispos ; 38(9): 553-556, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28866862

RESUMO

Acetylshikonin is a biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma. An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC50 values of 1.4-4.0 µ m. Pre-incubation of acetylshikonin with HLMs and NADPH did not alter the inhibition potency, indicating that acetylshikonin is not a mechanism-based inhibitor. SKF-525A, a widely used non-specific P450 inhibitor, had no inhibitory activity against CYP1A2, 2A6, 2E1 and 2J2, while it showed an inhibitory effect against CYP2B6, CYP2C19 and 2D6 with IC50 values of 2.5, 3.6 and 0.5 µ m, respectively. Our findings indicate that acetylshikonin may be a novel general P450 inhibitor, which could replace SKF-525A.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Antraquinonas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lithospermum/química , Microssomos Hepáticos/enzimologia , Proadifeno/farmacologia
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